Abstract
The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodeling in pulmonary hypertension (PH). It has been reported that miR-137 inhibits the proliferation of tumor cells. However, whether miR-137 is involved in PH remains unclear. In this study, male Sprague-Dawley rats were subjected to 10% O2 for 3 weeks to establish PH, and rat primary PASMCs were treated with hypoxia (3% O2) for 48 h to induce cell proliferation. The effect of miR-137 on PASMC proliferation and calpain-2 expression was assessed by transfecting miR-137 mimic and inhibitor. The effect of calpain-2 on PASMC proliferation was assessed by transfecting calpain-2 siRNA. The present study found for the first time that miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and in hypoxia-treated PASMCs. miR-137 mimic inhibited hypoxia-induced PASMC proliferation and upregulation of calpain-2 expression in PASMCs. Furthermore, miR-137 inhibitor induced the proliferation of PASMCs under normoxia, and knockdown of calpain-2 mRNA by siRNA significantly inhibited hypoxia-induced proliferation of PASMCs. Our study demonstrated that hypoxia-induced downregulation of miR-137 expression promoted the proliferation of PASMCs by targeting calpain-2, thereby potentially resulting in pulmonary vascular remodeling in hypoxic PH.
Highlights
Pulmonary hypertension (PH) is a rare vascular disorder, defined clinically as a mean pulmonary artery pressure over 25 mmHg at rest or over 30 mmHg during activity
This study represents the first evidence of the role of miR137 in mediating hypoxia-induced proliferation of pulmonary arterial smooth muscle cells (PASMCs), thereby potentially contributing to pulmonary arterial remodeling in PH
The main findings of the present study are as follows: (1) miR-137 was downregulated in pulmonary arteries of hypoxic PH rats and hypoxia-treated PASMCs; (2) miR-137 mimic inhibited hypoxia-induced proliferation of PASMCs by targeting calpain-2, and miR137 inhibitor induced the proliferation of PASMCs under normoxia; (3) knockdown of calpain-2 by small interfering RNA (siRNA) suppressed hypoxia-induced proliferation of PASMCs
Summary
Pulmonary hypertension (PH) is a rare vascular disorder, defined clinically as a mean pulmonary artery pressure (mPAP) over 25 mmHg at rest or over 30 mmHg during activity. Pulmonary vascular remodeling plays an important role in PH pathology, which is mainly characterized by endothelial cell injury, smooth muscle cell proliferation, fibroblast muscularization, extracellular matrix increase, in situ thrombosis, varying degree inflammation, and plexiform arterial changes [1, 2]. To fully reveal the role of miRNAs in hypoxic PH, we did the pilot microarray assay in pulmonary arteries of hypoxic PH rats and found that the expression of miR-137 was significantly downregulated. We hypothesize that miR-137 contributes to hypoxic PH by targeting calpain-2 and designed this study to explore the regulatory role of miR-137 in hypoxia-induced PASMC proliferation and pulmonary arterial remodeling in rat hypoxic PH, and the regulating effect of miR-137 on calpain-2 expression was certificated
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